The major purpose of this exploratory developmental study will be to lay the groundwork for a future R01 to conduct a pharmacogenetic (PGx) randomized controlled trial of smoking cessation - incorporating a patient- centered and effective genetic feedback (GF) motivational enhancement intervention. The rationale for conducting a feasibility trial is three-fold. First, converging data from multiple studies demonstrate replication of the observation that low activity dopaminergic genetic variants (e.g., ANKK1/ "DRD2" Taq1A A1 alleles) are associated with greater nicotine replacement therapy (NRT) efficacy and higher activity variants (e.g., Taq1A A2 alleles) are associated with greater sustained-release bupropion (BUP) efficacy for smoking cessation. Secondly, PGx smoking cessation therapies are currently directly marketed to smokers without evidence of safety and efficacy from prospective trials. Finally, to date, the only published studies of the psychological and behavioral impact of GF for smoking cessation PGx therapies have used hypothetical case studies in non- clinical settings. Therefore, our transdisciplinary team with expertise in PGx, clinical trials, biomarker-informed motivational enhancement, qualitative methods, and biomedical ethics, proposes the following specific aims: Aim 1: Conduct formative research to develop and refine a clinical protocol for a multi-component smoking cessation intervention, grounded in the extended parallel process model, consisting of PGx treatment and GF: We will adapt, pilot-test, and refine a theoretically-grounded PGx smoking cessation intervention using formative interviews of 20 African-American and European-ancestry smokers. Aim 2: Conduct a mixed-methods feasibility trial randomizing treatment-seeking smokers to PGx treatment combined with GF vs. PGx treatment without GF for smoking cessation to examine the feasibility of the newly developed protocol in a primary care setting and characterize its psychological and behavioral impact: Smokers (N = 100) will be randomized to GF vs. no GF and all will receive motivational interviewing (standard care/SC) and PGx treatment. We will assess the impact of GF on time to relapse, medication adherence, and a comprehensive assessment battery of process and cognitive, psychological, and behavioral outcomes. Finally, we will synthesize quantitative and qualitative data to revise protocols, generate hypothesizes, and estimate effect sizes for a follow-up R01 submission. We hypothesize that amongst smokers receiving PGx and SC, the addition of genetic feedback will be associated with increased time to relapse and medication adherence;and we will explore whether or not GF enhances self-efficacy, smoking cessation confidence, and perceived control over smoking cessation from baseline to follow-up assessments during treatment and at the end of treatment. PUBLIC HEALTH RELEVANCE: The results from this project will support our ability to conduct a large-scale, randomized clinical trial of prospective genetically tailored smoking cessation therapies, to be submitted as an R01 proposal. These results will facilitate the translation of the growing body of pharmacogenetic information from retrospective studies toward the ultimate goals of developing evidence-based, patient-centered, personalized smoking cessation therapies that enhance efficacy while minimizing the risk of adverse psychological or behavioral outcomes.